Fundaun 2026 — Serum NfL elevated in FM at levels comparable to small fiber neuropathy

One-paragraph summary

Multi-cohort case-control study quantifying serum neurofilament light chain (NfL) — the established blood biomarker of axonal injury — across four groups: 60 fibromyalgia, 61 endometriosis (traditionally non-neuropathic), 24 small fiber neuropathy (recognized neuropathic), and 30 healthy controls, using the high-sensitivity Simoa SR-X NF Light v2 digital immunoassay. Serum NfL was significantly elevated in fibromyalgia (8.52 pg/mL vs 6.77 pg/mL HC; p=0.048) at levels comparable to small fiber neuropathy (8.98 pg/mL; p=0.004), with endometriosis representing an intermediate phenotype. Z-score analysis controlling for age and BMI strengthened the FM finding (Z=-0.30 vs HC Z=-1.15; p=0.006). The NfL elevation did not correlate with painDETECT neuropathic-pain-likeness scores within the FM group, indicating NfL indexes neuronal injury irrespective of clinical pain phenotype. For the FM project, this paper supplies a serological objective biomarker of ongoing neuronal damage in fibromyalgia at levels comparable to a recognized neuropathic condition — direct, blood-based, fluid-biopsy evidence that FM is biologically associated with axonal injury, complementing the retinal nerve fiber layer thinning finding (Garcia-Martin 2016) and the corneal nerve fiber density reduction in FM. Critically, the paper explicitly cites skin biopsy IENFD and corneal confocal microscopy as adjacent SFN diagnostic modalities — situating serum NfL alongside the retinal-biomarker-priority panel as a blood-side companion measurement. NfL is a strong candidate for inclusion in the biomarker-mapping cohort's blood-marker module as a non-invasive multi-chain neural-injury readout.

Claims as triples

• serum_NfL_level — predicts → fibromyalgia [evidence: AUC-implied discrimination across 4-group comparison; confidence: emerging]
• fibromyalgia — correlates_with → axonal_injury [evidence: serum NfL elevated at SFN-comparable levels; confidence: emerging]
• NfL — present_in → fibromyalgia [direct ELISA detection in patient sera; confidence: established (in this cohort)]
• serum_NfL_level — present_in → small_fiber_neuropathy [evidence: positive control group; confidence: established]
• endometriosis — bridges → fibromyalgia [intermediate-phenotype finding for serum NfL; confidence: bridging]
• serum_NfL_level — absent_in → endometriosis [non-significant vs HC; confidence: emerging]

Methods note

Four-cohort cross-sectional comparison. Fibromyalgia cohort recruited from PAIN-less study team; endometriosis from ENDOx/EndoPain; SFN from neuropathy clinics; HC age-matched. Serum NfL measured by Quanterix Simoa SR-X NF Light v2 digital immunoassay (validated sub-pg/mL sensitivity). Statistical analysis: between-group comparisons controlling for age and BMI via Z-score normalization. Neuropathic-pain-likeness assessed via painDETECT (FM, endo) and NeuPSIG grading (SFN).

Limitations

• Cross-sectional design — cannot establish temporal direction of NfL elevation relative to FM onset or disease activity.
• FM cohort not stratified by anti-SGC IgG status, HαT, β2-AR autoantibodies, or other project-relevant chain markers — leaves Q-Re-2-style stratification analysis open.
• Effect sizes are modest (8.52 vs 6.77 pg/mL); clinically actionable cutoff would require larger validation cohorts.
• Endometriosis as comparator is unusual; standard comparators for FM (RA, OA, low back pain) would have been more directly informative for diagnostic specificity claims.

Open questions raised

• Does serum NfL correlate with OCT RNFL thinning (Garcia-Martin 2016) in the same FM patients? (Direct retinal-biomarker integration question — would combine the blood-side and imaging-side neural-injury markers into a joint biomarker.)
• Does serum NfL stratify by FM chain markers (anti-SGC IgG, HERV-W ENV, β2-AR Aab)? (Q-Re-2 extension.)
• Does serum NfL predict FM medication response (pregabalin, duloxetine, milnacipran)?
• Does serum NfL track disease activity longitudinally in FM, or is it a static trait marker?

Triangulation notes

• Complementary to Garcia-Martin 2016 RNFL thinning — both findings index objective neural-tissue injury in FM, one via blood, the other via retinal imaging. Their concordance in the same patient would strengthen both as biomarkers; their discordance would identify FM patients with central-only vs. peripheral-also injury patterns. Joint measurement is a priority for the biomarker-mapping cohort.
• Strengthens H3 chain at the molecular biomarker level: NfL is a classical CNS axonal-injury marker; its elevation in FM aligns with the project's emerging interpretation of FM as a chain capable of producing measurable neuroaxonal damage (consistent with the central-only chain framework and the Kerrebijn 2025 brain-tissue heritability anchor).
• Aligns with the retinal-biomarker-diagnostic-priority §6 panel design: NfL is the obvious blood-side addition to the OCT/OCTA/CCM imaging panel, providing molecular convergent evidence at low marginal cost.
• Cross-condition mapping: NfL elevation across FM ≈ SFN > endo > HC suggests a graded spectrum of neuronal injury rather than discrete disease categories — consistent with the project's chain framework allowing the same final-common-pathway biomarker across multiple upstream mechanisms.
• Connects to Giménez-Orenga 2025 panel (already in project as post_covid_differentiation_panel): that panel includes NfL as one of its components; Fundaun 2026 supplies the FM-direct anchor for NfL beyond the post-COVID context.

Bridges

• B-Re-4 (Serum NfL ↔ retinal RNFL thinning — joint neural-injury biomarkers, NEW 2026-05-23). Both endpoints FM-anchored (Fundaun 2026 + Garcia-Martin 2016). Confidence: emerging. Closing: joint measurement in same FM cohort; correlation would convert two independent biomarkers into a unified neural-injury panel.